NEW ZEALAND DATA SHEET

Transcription

1 NEW ZEALAND DATA SHEET 1 ORGALUTRAN 250 µg/0.5 ml solution for injection 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Ganirelix (as the acetate salt) 0.5 mg/ml. ORGALUTRAN contains the synthetic decapeptide ganirelix (INN) as its acetate salt, with high antagonistic activity to the naturally occurring gonadotropin releasing hormone (GnRH). Each prefilled syringe contains 250 µg ganirelix (as acetate) in 0.5 ml. The amino acids at positions 1, 2, 3, 6, 8 and 10 of the natural GnRH decapeptide have been substituted resulting in N-Ac-D-Nal(2) 1, D-pClPhe 2, D-Pal(3) 3, D-hArg(Et2) 6, L- harg(et2) 8, D-Ala 10 ]-GnRH with a molecular weight of For the full list of excipients, see 6.1 List of excipients. 3 PHARMACEUTICAL FORM ORGALUTRAN (ganirelix acetate) is presented as a sterile, ready for use, clear, colourless aqueous solution intended for subcutaneous administration. 4 CLINICAL PARTICULARS 4.1 Therapeutic indications The prevention of premature luteinizing hormone (LH) surges in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproduction techniques (ART). In clinical trials, ORGALUTRAN was used with recombinant follicle stimulating hormone (FSH). 4.2 Dose and method of administration ORGALUTRAN should only be prescribed by a specialist experienced in the treatment of infertility. Dosage ORGALUTRAN is used to prevent premature LH surges in patients undergoing COH. Controlled ovarian hyperstimulation with FSH may start at day 2 or 3 of menses. ORGALUTRAN (0.25 mg) should be injected subcutaneously once daily, starting on day 6 of FSH administration. In high responders an early LH rise may be prevented by starting ORGALUTRAN treatment on day 5. The start of ORGALUTRAN may be delayed in the absence of follicular growth. ORGALUTRAN and FSH should be administered at approximately the same time. However, the preparations should not be mixed and different injection sites are to be used. FSH dose ORGALUTRAN DS A (CCDS-MK8761-INJ ) Page 1 of 8

2 adjustments should be based on the number and size of growing follicles, rather than on the amount of circulating estradiol (see 5.1 Pharmacodynamic properties). Daily treatment with ORGALUTRAN should be continued up to the day that sufficient follicles of adequate size are present. Final maturation of follicles can be induced by administering human chorionic gonadotrophin (hcg). Because of the half-life of ganirelix, the time between two ORGALUTRAN injections as well as the time between the last ORGALUTRAN injection and the hcg injection should not exceed 30 hours, as otherwise a premature LH surge may occur. Therefore, when injecting ORGALUTRAN in the morning, treatment with ORGALUTRAN should be continued throughout the gonadotrophin treatment period including the day of triggering ovulation. When injecting ORGALUTRAN in the afternoon, the last ORGALUTRAN injection should be given in the afternoon prior to the day of triggering ovulation. ORGALUTRAN has been shown to be safe and effective in patients undergoing multiple treatment cycles. Luteal phase support should be given according to the reproductive medical centre s practice. Special Populations Use in hepatic impairment See 4.3 Contraindications. Use in renal impairment See 4.3 Contraindications. Use in the elderly No data available. Paediatric population There is no relevant use of ORGALUTRAN in the paediatric population. Effects on laboratory tests No data available Method of administration Inspect the solution before use. It must only be used if it is clear and without particulate matter. ORGALUTRAN should be administered subcutaneously, preferably in the upper leg. The injection site should be varied to prevent lipoatrophy. The patient or her partner may perform the injections of ORGALUTRAN themselves, provided that they are adequately instructed and have access to expert advice. 4.3 Contraindications - Hypersensitivity to the active substance or to any of the components including dry natural rubber/latex (see sections 6.1 List of excipients and 6.5 Nature and contents of container). ORGALUTRAN DS A (CCDS-MK8761-INJ ) Page 2 of 8

3 - Hypersensitivity to GnRH or any other GnRH analogue - Moderate or severe impairment of renal or hepatic function - Pregancy or lactation 4.4 Special warnings and precautions for use Special care should be taken in women with signs and symptoms of active allergic conditions. Cases of hypersensitivity reactions have been reported, as early as with the first dose, during post-marketing surveillance (see 4.8 Undesirable Effects). In the absence of clinical experience, ORGALUTRAN treatment is not advised in women with severe allergic conditions. The needle shield of ORGALUTRAN contains dry natural rubber/latex which comes into contact with this product and may cause allergic reactions (see sections 4.3 Contraindications and 6.5 Nature and contents of this container). Ovarian hyperstimulation syndrome (OHSS) may occur during or following ovarian stimulation. OHSS must be considered an intrinsic risk of gonadotrophin stimulation. OHSS should be treated symptomatically, e.g. with rest, intravenous infusion of electrolyte solutions or colloids and heparin. Since infertile women undergoing assisted reproduction, and particularly IVF, often have tubal abnormalities the incidence of ectopic pregnancies might be increased. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important. The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be slightly higher than after spontaneous conceptions. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g. maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. There are no indications that the use of GnRH antagonists during ART is associated with an increased risk of congenital malformations. In clinical trials investigating more than 1000 newborns it has been demonstrated that the incidence of congenital malformations in children born after COH treatment using ORGALUTRAN is comparable with that reported after COH treatment using a GnRH agonist. The safety and efficacy of ORGALUTRAN have not been established in women weighing less than 50 kg or more than 90 kg (see also 5.1 Pharmacodynamic properties and 5.1 Pharmacokinetic properties). 4.5 Interactions with other medicines and other forms of interactions Interactions of ORGALUTRAN with other medicines have not been investigated; interactions with commonly used medicinal products, cannot therefore be excluded. 4.6 Fertility, pregnancy and lactation Fertility Ganirelix treatment of female rats resulted in reversible impairment of mating and fertility at a subcutaneous dose of 2.5 µg/kg/day, and reversible cessation of mating was seen in males treated with a subcutaneous dose of 0.1 mg/kg/day. ORGALUTRAN DS A (CCDS-MK8761-INJ ) Page 3 of 8

4 Pregnancy (Category D) ORGALUTRAN is not intended to be used during pregnancy (see 4.3 Contraindications). No clinical data on exposed pregnancies are available. In animals, exposure to ganirelix at the time of implantation resulted in litter resorption (see 5.3 Preclinical Safety Data). The relevance of these data for humans is unknown. Breast-feeding ORGALUTRAN should not be used by lactating women (see 4.3 Contraindications). It is not known whether ganirelix is excreted in breast milk. 4.7 Effects on ability to drive and use machines The effects of ORGALUTRAN on ability to drive and use machines have not been studied. 4.8 Undesirable effects General disorders and administration site conditions ORGALUTRAN may cause a local skin reaction at the site of injection (predominantly redness, with or without swelling). In clinical studies, one hour after injection, the incidence of at least once of a moderate or severe local skin reaction per treatment cycle was 12% in ORGALUTRAN treated patients and 25% in patients treated subcutaneously with a GnRH agonist. The local reactions generally disappear within 4 hours after administration. Malaise was reported in 0.3% of patients. Immune system disorders Very rarely, post-marketing cases of hypersensitivity reactions (including various symptoms such as rash, facial swelling and dyspnoea) have been reported, as early as with the first dose, among patients administered ORGALUTRAN. Nervous system disorders Headache (0.4%). Gastrointestinal disorders Nausea (0.5%). Other reported undesirable effects are related to the controlled ovarian hyperstimulation treatment for ART, notably pelvic pain, abdominal distension, OHSS, ectopic pregnancy and spontaneous abortion (see also section 4.4 Special warnings and precautions for use). Reporting suspected adverse reactions Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at ORGALUTRAN DS A (CCDS-MK8761-INJ ) Page 4 of 8

5 4.9 Overdose Overdose in humans may result in a prolonged duration of action. In case of overdose, ORGALUTRAN treatment should be (temporarily) discontinued. No data on acute toxicity of ORGALUTRAN in humans are available but it is unlikely that toxic effects will occur. Clinical studies with subcutaneous administration of ORGALUTRAN at single doses up to 12mg did not show undesirable systemic side-effects. In acute toxicity studies in rats and monkeys non-specific toxic symptoms were only observed after intravenous administration of ganirelix over 1 and 3 mg/kg, respectively. For advice on the management of overdose please contact the National Poisons Centre on 0800 POISON ( ). 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: anti-gonadotrophin releasing hormone; ATC code: H01CC01. Mechanism of action ORGALUTRAN is a gonadotrophin-releasing hormone (GnRH) antagonist, which modulates the hypothalamic-pituitary-gonadal axis by competitive binding to the GnRH receptors in the pituitary gland. As a result a rapid, profound, reversible suppression of endogenous gonadotrophins occurs, without initial stimulation as induced by GnRH agonists. Clinical Trials Following administration of multiple doses of 0.25 mg ORGALUTRAN to female volunteers serum LH, FSH and E2 concentrations were maximally decreased by 74%, 32% and 25% at 4, 16 and 16 hours after injection, respectively. Serum hormone levels returned to pretreatment values within two days after the last injection. In patients undergoing controlled ovarian stimulation the median duration of ORGALUTRAN treatment was 5 days. During ORGALUTRAN treatment the average incidence of LH rises (>10 IU/l) with concomitant progesterone rise (>1 ng/ml) was 1.2% compared to 0.8% during GnRH agonist treatment. Early LH rises, prior to the start of ORGALUTRAN at day 6 of stimulation, did occur especially in high responders, but did not affect the clinical outcome. In these patients LH production was rapidly suppressed after the first ORGALUTRAN administration. In controlled studies of ORGALUTRAN, using a long protocol of GnRH agonist as a reference, treatment with the ORGALUTRAN regimen resulted in a faster follicular growth during the first days of stimulation, but the final cohort of growing follicles was slightly smaller and produced on average less oestradiol. This different pattern of follicular growth requires that FSH dose adjustments are based on the number and size of growing follicles, rather than on the amount of circulating estradiol. 5.2 Pharmacokinetic properties Absorption After a single subcutaneous administration of 0.25 mg, serum levels of ganirelix rise rapidly and reach peak levels (Cmax) of approximately 15 ng/ml within 1 to 2 hours (tmax). ORGALUTRAN DS A (CCDS-MK8761-INJ ) Page 5 of 8

6 Pharmacokinetic parameters after multiple subcutaneous dosing of ORGALUTRAN (once daily injection) were similar to those after a single subcutaneous dose. After repeated dosing 0.25 mg/day steady-state levels of approximately 0.6 ng/ml were reached within 2 to 3 days. The bioavailability of ORGALUTRAN following subcutaneous administration is approximately 91%. Distribution Pharmacokinetic analysis indicates an inverse relationship between bodyweight and serum concentrations of ORGALUTRAN. Biotransformation The major circulating component in plasma is ganirelix. Ganirelix is also the main compound found in urine. Faeces contained only metabolites. The metabolites are small peptide fragments formed by enzymatic hydrolysis of ganirelix at restricted sites. The metabolite profile of ORGALUTRAN in humans was similar to that found in animals. Elimination After a single subcutaneous administration of 0.25 mg, the elimination half-life (t½) is approximately 13 hours and clearance is approximately 2.4 L/h. Excretion occurs via faeces (approximately 75%) and urine (approximately 22%). 5.3 Preclinical safety data Preclinical data reveal no special hazard for humans based on safety pharmacology, repeated dose toxicity and genotoxicity. Reproduction studies carried out with ganirelix at doses of 0.1 to 10 µg/kg/day subcutaneously in the rat and 0.1 to 50 µg/kg/day subcutaneously in the rabbit showed increased litter resorption in the highest dose groups. No teratogenic effects were observed. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients The ORGALUTRAN solution for injection contains acetic acid, mannitol and water for injections. The ph may have been adjusted with sodium hydroxide and acetic acid. 6.2 Incompatibilities In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 36 months when stored between 2 C and 30 C, in the original package. ORGALUTRAN DS A (CCDS-MK8761-INJ ) Page 6 of 8

7 6.4 Special precautions for storage Do not freeze. Store between 2 C and 30 C. Store in the original package in order to protect from light. 6.5 Nature and contents of container ORGALUTRAN is presented as a sterile, ready for use, aqueous solution and supplied in disposable pre-filled syringes (siliconised Type I glass), containing 0.5 ml closed with a rubber piston that does not contain latex. Each pre-filled syringe is affixed with a needle closed by a needle shield of dry natural rubber/latex which comes into contact with this product. (See sections 4.3 Contraindications and 4.4 Special warnings and precautions for use). Supplied in cartons containing 1 or 5 pre-filled syringes. 6.6 Special precautions for disposal and other handling Inspect the solution before use. It must only be used if it is clear and without particulate matter. This product is for single use only. Discard any remaining contents. Any unused product or waste material should be disposed of in accordance with local requirements. 7 MEDICINE SCHEDULE (POISONS STANDARD) Prescription Medicine 8 SPONSOR Merck Sharp & Dohme (NZ) Ltd P O Box Newmarket Auckland 1149 Tel: DATE OF FIRST APPROVAL 26 July DATE OF REVISION 12 June 2018 ORGALUTRAN DS A (CCDS-MK8761-INJ ) Page 7 of 8

8 SUMMARY TABLE OF CHANGES Section Changed All sections 4.3, 4.4, 6.5 Summary of new information Reformatted Data Sheet to new Medsafe template. Additional precautionary information regarding potential hypersensitivity to dry natural rubber/latex. ORGALUTRAN DS A (CCDS-MK8761-INJ ) Page 8 of 8